Adaptive immunity to pathogens hinges upon separate processes for short- and long-term increases in the activity of antigen-specific B and T lymphocytes. Short-term multiplication and differentiation of plasma cells and cytotoxic T cells is critical for resolving an existing infection, but the strength of the immediate response needs to be balanced with the processes that establish long-term immunity such as affinity maturation, formation of memory B and T cells, and differentiation of long-lived bone marrow plasma cells. Much remains unknown about the genetic and systems-level decision-making that guides these short- and long-term processes. Without that understanding there are major gaps in strategies to establish and improve vaccines against many NIH Priority Pathogens, and to interpret patterns of human genetic, cellular, and serological variation to predict the efficacy and longevity of immunity in clinical settings and in the field. This project, in synergy with the Cores and other projects of this U19 program, will expand the community resource of mouse mutations and datasets that experimentally connect discrete genes with the cells and systems governing short- and long-term adaptive immunity. These resources and datasets will be distributed to the community via repositories and websites to enable researchers to test their own hypotheses about adaptive immunity. In addition, the project will focus on a subset of novel gene mutations affecting memory versus effector decisions or antibody affinity maturation in the context of immunity to NIH Priority Pathogens, and determine the cellular and molecular systems controlled by these genes.